The association between dairy intake and migraine odds among pediatrics and adolescents: A case-control study

Objective Migraine is recognized as a disease with unknown etiology and various pathophysiologic pathways which are not fully understood. Due to the relation between dairy intake and various chronic conditions in children and also the paucity of data on the probable role of dairy intake on pediatrics’ odds of having migraine, this study was designed. Materials & Methods: The present study was a population-based case-control design that was accomplished in a tertiary headache clinic.290 child (aged from7 to 14 years old) was included in this study. A definite diagnosis of migraine was performed by a neurologist; concerning the 2018 international classification of headache disorder 3 (ICHD3) criteria. Also, demographic and anthropometric characteristics were obtained. In addition, the usual dietary intake of participants was evaluated using a validated semi-quantitative food frequency questionnaire (FFQ). Results Those children in the case group significantly had higher age and BMI means (P.value:0.000). In the second regression model, odds of migraine were 48% (OR: 0.52; 95%CI:0.27-1.00) diminished in the second tertile and 53% (OR:0.47;95%CI:0.24-0.92) in the third tertile of low-fat dairy intake (P-trend:0.03). In the fully adjusted model, the achieved migraine ORs were as followings:0.48 (95% CI:0.240.95) in the second tertile and 0.46 (95% CI:0.21-0.96) in the third tertile (P-trend:0.04), respectively. Children with more high-fat dairy intake also consumed higher amounts of energy, pastries, simple sugar, unhealthy snacks, and hydrogenated oil (P<0.05). Conclusion: This study results proposed that a greater amount of low-fat dairy intake may attenuate the odds of having migraine attacks in pediatrics and adolescents who might be at risk of headache, which can be attributed to the micronutrient and also to the bioactive content of these dietary components.


Introduction
Migraine is recognized as the first disabling neurological condition, which is characterized by recurring, pulsating, and unilateral headache attacks Goadsby, Lipton (1). Migraine headaches are identified as a prevalent disorder amongst adults, and it has been established as a common phenomenon in school-aged children. The mean prevalence of migraine in children and adolescents is estimated to be 9.1% globally (2). However, the prevalence rate might be different concerning the diagnostic criteria that are used to detect migraine in the targeted age group. A migraine headache can have a potentially negative effect on the quality of life as an incapacitating disease, in pediatrics and adolescents. Impairment in academic functioning, school attendance, and social interactions are all results of migraine headaches in school-aged children (3,4).
Migraine pathophysiology as a complex neurogenic disorder is still not fully understood. It has been asserted that genetic factors are involved in migraine pathophysiology (5); however, environmental factors like diet and lifestyle-related factors may have been considered as potential risk factors for headaches in migraineurs (6). Moreover, both vascular and neural mechanisms are hypothesized to be involved in this disorder.
Although the available evidence does not confirm the migraine exact mechanism, inflammation and vasodilation have been suggested to be involved in the migraine attack's pathogenesis (7). food intolerance in migraineurs, and out of them avoidance from certain food allergens was the center of the debate. Concerning the probable effect of dietary components in migraine patients, some dairy products including processed cheese, whole milk, and ice cream were categorized as foods to be avoided since they might not be tolerated in those individuals with migraine. Consequently, as an alternative, low-fat milk could be considered a safe choice for migraineurs. On the other hand, particular nutrients found in different foods and beverages might indicate a protective role against headaches in migraineurs including magnesium, calcium, phosphorous, and vitamin D (8).

Dairy products are identified as abundant sources
of various micronutrients and other bioactive compounds named calcium, phosphorous, magnesium, vitamin B12, vitamin B2, and vitamin D (9). Therefore, adherence to a diet, which is low in dairy intake, can adversely affect health status, particularly in children and adolescents (10).
Several investigations have demonstrated a reverse association between adequate dairy consumption and chronic disease risk (11). Recently published research indicated that dairy intake could decrease migraine development through anti-inflammatory pathways since these products are rich sources of antioxidant vitamins and minerals. (8,12).
While the recent investigations have shed light on the possible impact of dairy intake on reducing the development of migraine headache in those adult individuals with migraine (6,8,12), scarce evidence exists about the possible association between having migraine headaches and dietary dairy intake in school-aged children and also adolescents. Also, due to the effective role of dairy in reducing low-grade inflammation (13) and gut microbiome balance (14) It can be hypothesized that higher consumption of these food items can be beneficial in reducing odds of inflammatoryrelated conditions such as migraine. Available evidence suggests that dairy product consumption is in association with higher micronutrient intake in children and adolescents and can be indicative of healthier eating habits (15). Regarding the importance of adequate micronutrient intake in the regulation of inflammatory pathways and subsequent influence on migraine pathogenesis, dairy intake might be beneficial in pediatric migraine odds. Therefore, this study concentrated on the association between dairy consumption and the risk of having migraine in pediatrics and adolescents.

Study participants
This population-based case-control study's purpose was to investigate the association between dietary dairy consumption and the odds of having migraine in 290 children and adolescent participants (aged from 7 to 14 years old). One hundred school-age children with migraine referred to either the tertiary referral clinic of Sina

Demographic and Anthropometric Assessments
After considering the inclusion and exclusion Height was measured using a measuring tape with a precision of 1 cm, at the time that participants were in a standing position without shoes and as shoulders were aligned normally. Body mass index (BMI) was calculated with the division of weight (kg) by the square of height (m2).

Dietary Assessments
All participants' usual dietary intakes were evaluated applying a semi-quantitative 168-item food frequency questionnaire (FFQ). The FFQ also had been earlier approved concerning validity and reliability in Iran. The questionnaire was administered by an experienced dietitian throughout a face-to-face interview. It included 168 separate food items with defined and standardized portion sizes (18). The participants were requested to report their annual consumption rate on a daily, weekly, monthly, and yearly basis for each food item.
Concerning the children's inability to fully recall each question, we asked their parents to cooperate through the interview to minimize the chance of recall bias. All the questions were asked in person from parents, while children were also present during the interview and none of the participants was required to complete the questionnaire on their  (240cc) (20). Additionally, we categorized total dairy intake into low-fat dairy (including low-fat milk (ml/day), low-fat yogurt (ml/day), feta cheese (g/day), and doogh (ml/day)) and high-fat dairy (including high-fat milk (ml/day), high-fat yogurt (ml/day), creamy yogurt (ml/day), creamy cheese (g/day), and kashk (ml/day).

Protocol approval and patient consent
This study protocol was approved by the Iranian

Center of Neurological Research, Neuroscience
Institute (research number=97-01-54-38173), and also by the ethics committee of Tehran University of medical science (ethical code number: IR.TUMS.

VCR.REC.1397-263). Participants' parents were
formally notified about this research purpose in detail and also were requested to sign a written informed constantly at this study onset.

Statistical analysis
The sample size of the study was based on our previous experience with this design and no statistical power calculation was conducted before the initiation of the study. Data analysis was performed using SPSS software (version 21 SPSS, Chicago, IL, USA). In addition, the Kolmogorov-Smirnov test was performed to determine the normal distribution of variables, after that independent two-sample t-test or Mann-Whitney U test was applied concerning the normal distribution. Categorical variables were compared by the use of the chi-square test. The main variables were stratified into tertiles cutoff points due to the study population. In addition, models of logistic regression were applied to estimate the association between migraine headache and dairy intake. After that, the odds ratio (OR) with 95% confidence interval (95%CI) was calculated for all tertiles, with the first tertile that was introduced as the reference group. The potential confounders were controlled by binary logistic regression models across categories, P for trends was calculated by computing the median value of each tertile of dairy products, and they were considered as a continuous variable. The significance level was considered as a P value less than 0.05.

Results
One hundred pediatric and adolescent migraine cases (51 female, and 49 male), and 190 healthy controls (91 female, and 99 male) were enrolled in this case-control study. Also, those children in the case group significantly had higher age and  Table 3 indicates the participant's mean daily intakes of dairy products concerning the tertiles of total dairy consumption. Children in higher tertiles of total dairy intake tended to have a significantly higher consumption of low-fat milk, high-fat milk, low-fat yogurt, high-fat yogurt, feta cheese, and doogh (P. value: 0.000). By low-fat milk, we meant 1.5% fat milk, that contained 1g fat, 5g carbohydrate, and 3.4 g protein in each 100 g of the product and for high-fat milk assessment, we considered 3.5% fat milk that contains 3.3 g fat, 4.8 g carbohydrate, and 3.2 g protein. Low-fat yogurt is also considered as 1.5% fat yogurt, with fat, carbohydrate, and protein content of 1.33 g, 7.11 g, and 4.88 g respectively in each 100 g of the product. Full fat yogurt is considered a 3.5% fat product, consisting of 3.67 g fat, 5 g carbohydrate, and 4 g protein in every 100 g of the product. Each It was observed that those subjects with higher consumption of total or low-fat dairy products tended to have increased energy, vegetables, fruits, and red meat intake. Those who had more highfat dairy products intake were also indicated to consume higher amounts of energy, whole grains, cakes and pastries, simple sugar, unhealthy snacks, and hydrogenated oil, during they consumed less refined grains (P.value <0.05).
The associations between having migraine and total dairy, low-fat dairy, and high-fat dairy daily intakes were estimated by the use of three logistic regression models [ Table 5]. Although there was no significant association between total dairy intake or high-fat dairy intake and odds of having migraine, it was established that a higher intake of low-fat dairy was accompanied by a reduction in migraine risk even after controlling for confounding factors and also different foods dietary intakes. The median intakes of low-fat respectively. Furthermore, a significant reduction in odds of migraine was observed in both second and third tertiles of low-fat dairy consumption vs. the first tertile, respectively, after considering confounding variables in the regression models. In the second model, which was adjusted for BMI and total energy intake in addition to age and gender, it was indicated that odds of migraine diminished by All data are presented as Mean (Standard Deviation) P-value was calculated using Independent sample T-test *An Asian product which is a mixture of water and yogurt ** An Asian product derived from drained sour yogurt or sour milk concentrates, known as a whey source. P.value was calculated using general linear model All data are presented as Mean (Standard Deviation) *An Asian product which is a mixture of water and yogurt ** An Asian product derived from drained sour yogurt or sour milk concentrates, known as a whey source. ¥ These value are presented as median $ P-trend was calculated using logistic regression model by considering the median of each tertile of total dairy/lowfat dairy/high-fat dairy intake as a continuous variable. 1 regression model adjusted for age and gender 2 regression model adjusted for age, gender, BMI, total energy intake 3 regression model adjusted for age, gender, BMI, total energy, refined grain, whole grain, cakes and pastries, simple sugar, vegetables, fruits, unhealthy snacks, poultry, fish, processed meat, red meat, butter and cream, and hydrogenated oil intake.

Discussion
According to our findings children who were in the control group appeared to have a higher intake The results of one previous study showed that dairy consumption can induce an anti-inflammatory effect through inhibition of nuclear factor κB (30).
Some studies claimed that hyperactivity of nuclear factor-κB can promote hypothalamic inflammation which is strongly related to migraine (31). In our study higher amounts of dairy products was associated with a lower risk of having migraine.
As it was mentioned before, dairy products are also The levels of these metabolites can be influenced by dietary items such as probiotics (36).
It is also noteworthy to state that the Lactobacillus content of fermented dairy products, which is the most frequent probiotic found in yogurt, is Also, we found that those with higher high-fat dairy products intake are more likely to consume some unhealthy foods. This is associated with a higher probability of weight gain in children with ages ranging from 5 to 7 years old (42